Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic Inflammation

Abstract

Aberrant gastric inflammation damages the stomach and induces gastric metaplasia (spasmolytic polypeptideexpressing metaplasia). Increased expression of the RNA binding protein tristetraprolin suppresses adrenalectomyinduced gastric inflammation and spasmolytic polypeptideexpressing metaplasia development. BACKGROUND & AIMS:Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a wellestablished sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin (TTP) is an RNAbinding protein that promotes the turnover of numerous proinflammatory and oncogenic messenger RNAs. Here, we assess the role of TTP in regulating gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) development. METHODS:We used a TTP-overexpressing model, the TTPDadenylate-uridylate rich element mouse, to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and SPEM. RESULTS:We found that TTPDadenylate-uridylate rich element mice were completely protected from ADX-induced gastric inflammation and SPEM. RNA sequencing 5 days after ADX showed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Importantly, TTP overexpression did not protect from highdose-tamoxifen-induced SPEM development, suggesting that protection in the ADX model is achieved primarily by suppressing inflammation. Finally, we show that protection from gastric inflammation was only partially due to the suppression of Tnf, a well-known TTP target. CONCLUSIONS:Our results show that TTP exerts broad antiinflammatory effects in the stomach and suggest that therapies that increase TTP expression may be effective treatments of proneoplastic gastric inflammation. Transcript profiling:

Comparison of gastric inflammation and metaplasia induced byHelicobacter pyloriorHelicobacter feliscolonization in mice

“…Next, we assessed the gastric immune-cell landscape 2 months post-challenge to determine how these bacterial species affect gastric inflammation. Immunostaining of the gastric corpus with the common leukocyte antigen CD45 revealed relatively few immune cells in the mock-challenged stomach, which is consistent with previous reports that the healthy stomach harbors relatively few resident leukocytes (Figure 2A) (29, 30) . HP infection induced modest leukocyte infiltration within the gastric corpus.…”

“…Chronic inflammation is necessary and sufficient for gastric cancer initiation. Mice that lack mature B and T cells are protected from morphological changes to the gastric epithelium in response to infection by either HP or HF (8, 43) , and myeloid cell activation is required for pyloric metaplasia initiation (29, 30, 44) . Moreover, overexpression of the proinflammatory IL1B or IFN-gamma under control of the parietal cell-specific H+/K+ ATPase β promoter drives gastric neoplasia development without accompanying Helicobacter infection (4, 5) .…”

Endogenous glucocorticoids are required for normal macrophage activation and gastricHelicobacter pyloriimmunity

“…In addition, our findings underscore the critical role that gastric macrophages play in the immune response to H. pylori, where they impact the T cell response and promote gastric atrophy and metaplasia development. These findings, combined with previous reports (15, 17, 49) , demonstrate that glucocorticoid signaling is important for regulating gastric immunity and may impact gastric cancer risk.…”